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A Randomized Trial Comparing Activated Thromboplastin Time With Heparin Assay in Patients With Acute Venous Thromboembolism Requiring Large Daily Doses of Heparin

A Randomized Trial Comparing Activated Thromboplastin Time With Heparin Assay in Patients With... Abstract Background: The management of heparin therapy in patients who have a subtherapeutic activated partial thromboplastin time (APTT) despite high doses of heparin is problematic because the risk of heparin-associated bleeding increases with dose. Results of experimental studies in animals indicate that when the APTT response to heparin is blunted by infusion of procoagulants, dose escalation can be avoided without compromising efficacy, by monitoring treatment with a heparin assay. Methods: A randomized, controlled trial was conducted in which patients with acute deep vein thrombosis, pulmonary embolism, or axillary vein thrombosis who required 35 000 U or more of intravenous heparin by continuous infusion during the previous 24 hours were allocated to have their heparin therapy monitored either by anti-factor Xa levels (targeted range, 0.35 to 0.67 U/mL) or by the APTT (targeted range, 60 to 85 seconds). Both ranges were equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration. Results: Three (4.6%) of 65 patients in the anti-factor Xa group experienced recurrent venous thromboembolism compared with four (6.1%) of 66 patients in the APTT group (difference, 1.5%; confidence interval, —6.7% to 8.4%) (P=.7). There were four bleeding events (6.1%) in the APTT group compared with one (1.5%) in the anti— factor Xa group (difference, 4.6%; confidence interval, —3.3% to 7.5%) (P=.4). During the period of heparin therapy before warfarin treatment was begun, the patients in the APTT group required a statistically significantly greater amount of heparin compared with the patients in the anti—factor Xa group. The daily mean APTT was subtherapeutic in patients in the anti—factor Xa group, and it was within the therapeutic range in the APTT group. The daily mean anti—factor Xa levels for both groups were within the therapeutic range. Conclusion: The heparin assay is a safe and effective method for monitoring heparin treatment in patients with acute venous thromboembolism whose APTT remains subtherapeutic despite large daily doses of heparin. In such patients, dosage escalation can be avoided if the heparin level is therapeutic.(Arch Intern Med. 1994;154:49-56) References 1. Barritt DW, Jordon SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial . Lancet . 1960;1:1309-1312.Crossref 2. Hirsh J. Heparin . N Engl J Med . 1991;324:1565-1574.Crossref 3. Hirsh J, van Aken WG, Gallus AS, Dollerey CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism . Circulation . 1976; 53:691-695.Crossref 4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis . N Engl J Med . 1986;315:1109-1114.Crossref 5. Hirsh J, Genton E, Hull R. Venous Thromboembolism . New York, NY: Grune & Stratton Inc; 1981:155-183. 6. Rosenberg RD. The heparin-antithrombin system: a natural anticoagulant mechanism . In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice . 2nd ed. Philadelphia, Pa: JB Lippincott Co; 1987:1373-1392. 7. Morabia A. Heparin doses and major bleeding . Lancet . 1986;1:1278-1279.Crossref 8. Levine MN, Hirsh J, Kelton JG. Heparin-induced bleeding . In: Lane DA, Lindahl U, eds. Heparin . Boca Raton, Fla: CRC Press; 1989:517-531. 9. Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin . Eur J Clin Pharmacol . 1990;39:107-112.Crossref 10. Doyle DJ, Turpie AGG, Hirsh J, Levine M, Gent M. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial . Ann Intern Med . 1987;107:441-445.Crossref 11. Gallus A, Jackaman J, Tillet J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism . Lancet . 1986;2:1293-1296.Crossref 12. Pini M, Pattachini C, Quintavalla R, et al. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis: a randomized clinical trial . Thromb Haemost . 1990;64:222-226. 13. Prandoni P, Lensing AW, Buller HR, et al. Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep vein thrombosis . Lancet . 1992;339:441-445.Crossref 14. Edson VR, Krivit W, White JG. Kaolin partial thromboplastin time: high levels of procoagulants produce short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants . J Lab Clin Med . 1967; 70:463-470. 15. Rickles FR, Edwards RL, Barb C, Crolund M. Abnormalities of blood coagulation in patients with cancer . Cancer . 1983;51:301-307.Crossref 16. Chiu HM, Hirsh J, Yung WL, et al. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis . Blood . 1977;49:171-184. 17. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for five days as compared with ten days in the initial treatment of proximal venous thrombosis . N Engl J Med . 1990;322:1260-1264.Crossref 18. Cruickshank M, Levine M, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy . Arch Intern Med . 1991; 151:333-337.Crossref 19. Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin . Am J Clin Pathol . 1961;36:212-219. 20. Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X . Thromb Res . 1976;8:410-416. 21. Biggs R. Human Blood Coagulation, Haemostasis and Thrombosis . Oxford, England: Blackwell Scientific Publishers; 1972. 22. Kahle LH, Schipper HG, Jenkins CSP, ten Cate JW. Antithrombin III evaluation of an automated antithrombin III method . Thromb Res . 1978;12:1003-1014.Crossref 23. Laurell CB. Quantitative estimation of proteins by electrophoresis in antibody-containing agarose gel . Anal Biochem . 1965;10:358.Crossref 24. Rossi E, Mondonico P, Lombari A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometers . Thromb Res . 1988;52:453-468.Crossref 25. Hull R, Carter C, Jay R, et al. The diagnosis of acute recurrent deep vein thrombosis: a diagnostic challenge . Circulation . 1983;67:901-906.Crossref 26. Hull R, Hirsh J, Carter C, et al. Pulmonary angiography, ventilation lung scanning and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan . Ann Intern Med . 1983;98:891-899.Crossref 27. Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer . Am J Clin Pathol . 1988;89:19-23. 28. Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidinerich glycoprotein: mechanism and role in the neutralization of heparin in plasma . J Biol Chem . 1983;258:3803-3808. 29. Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins: an important mechanism for heparin resistance . Thromb Haemost . 1992;67:639-643. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

A Randomized Trial Comparing Activated Thromboplastin Time With Heparin Assay in Patients With Acute Venous Thromboembolism Requiring Large Daily Doses of Heparin

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Publisher
American Medical Association
Copyright
Copyright © 1994 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1994.00420010073009
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Abstract

Abstract Background: The management of heparin therapy in patients who have a subtherapeutic activated partial thromboplastin time (APTT) despite high doses of heparin is problematic because the risk of heparin-associated bleeding increases with dose. Results of experimental studies in animals indicate that when the APTT response to heparin is blunted by infusion of procoagulants, dose escalation can be avoided without compromising efficacy, by monitoring treatment with a heparin assay. Methods: A randomized, controlled trial was conducted in which patients with acute deep vein thrombosis, pulmonary embolism, or axillary vein thrombosis who required 35 000 U or more of intravenous heparin by continuous infusion during the previous 24 hours were allocated to have their heparin therapy monitored either by anti-factor Xa levels (targeted range, 0.35 to 0.67 U/mL) or by the APTT (targeted range, 60 to 85 seconds). Both ranges were equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration. Results: Three (4.6%) of 65 patients in the anti-factor Xa group experienced recurrent venous thromboembolism compared with four (6.1%) of 66 patients in the APTT group (difference, 1.5%; confidence interval, —6.7% to 8.4%) (P=.7). There were four bleeding events (6.1%) in the APTT group compared with one (1.5%) in the anti— factor Xa group (difference, 4.6%; confidence interval, —3.3% to 7.5%) (P=.4). During the period of heparin therapy before warfarin treatment was begun, the patients in the APTT group required a statistically significantly greater amount of heparin compared with the patients in the anti—factor Xa group. The daily mean APTT was subtherapeutic in patients in the anti—factor Xa group, and it was within the therapeutic range in the APTT group. The daily mean anti—factor Xa levels for both groups were within the therapeutic range. Conclusion: The heparin assay is a safe and effective method for monitoring heparin treatment in patients with acute venous thromboembolism whose APTT remains subtherapeutic despite large daily doses of heparin. In such patients, dosage escalation can be avoided if the heparin level is therapeutic.(Arch Intern Med. 1994;154:49-56) References 1. Barritt DW, Jordon SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial . Lancet . 1960;1:1309-1312.Crossref 2. Hirsh J. Heparin . N Engl J Med . 1991;324:1565-1574.Crossref 3. Hirsh J, van Aken WG, Gallus AS, Dollerey CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism . Circulation . 1976; 53:691-695.Crossref 4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis . N Engl J Med . 1986;315:1109-1114.Crossref 5. Hirsh J, Genton E, Hull R. Venous Thromboembolism . New York, NY: Grune & Stratton Inc; 1981:155-183. 6. Rosenberg RD. The heparin-antithrombin system: a natural anticoagulant mechanism . In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice . 2nd ed. Philadelphia, Pa: JB Lippincott Co; 1987:1373-1392. 7. Morabia A. Heparin doses and major bleeding . Lancet . 1986;1:1278-1279.Crossref 8. Levine MN, Hirsh J, Kelton JG. Heparin-induced bleeding . In: Lane DA, Lindahl U, eds. Heparin . Boca Raton, Fla: CRC Press; 1989:517-531. 9. Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin . Eur J Clin Pharmacol . 1990;39:107-112.Crossref 10. Doyle DJ, Turpie AGG, Hirsh J, Levine M, Gent M. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial . Ann Intern Med . 1987;107:441-445.Crossref 11. Gallus A, Jackaman J, Tillet J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism . Lancet . 1986;2:1293-1296.Crossref 12. Pini M, Pattachini C, Quintavalla R, et al. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis: a randomized clinical trial . Thromb Haemost . 1990;64:222-226. 13. Prandoni P, Lensing AW, Buller HR, et al. Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep vein thrombosis . Lancet . 1992;339:441-445.Crossref 14. Edson VR, Krivit W, White JG. Kaolin partial thromboplastin time: high levels of procoagulants produce short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants . J Lab Clin Med . 1967; 70:463-470. 15. Rickles FR, Edwards RL, Barb C, Crolund M. Abnormalities of blood coagulation in patients with cancer . Cancer . 1983;51:301-307.Crossref 16. Chiu HM, Hirsh J, Yung WL, et al. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis . Blood . 1977;49:171-184. 17. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for five days as compared with ten days in the initial treatment of proximal venous thrombosis . N Engl J Med . 1990;322:1260-1264.Crossref 18. Cruickshank M, Levine M, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy . Arch Intern Med . 1991; 151:333-337.Crossref 19. Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin . Am J Clin Pathol . 1961;36:212-219. 20. Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X . Thromb Res . 1976;8:410-416. 21. Biggs R. Human Blood Coagulation, Haemostasis and Thrombosis . Oxford, England: Blackwell Scientific Publishers; 1972. 22. Kahle LH, Schipper HG, Jenkins CSP, ten Cate JW. Antithrombin III evaluation of an automated antithrombin III method . Thromb Res . 1978;12:1003-1014.Crossref 23. Laurell CB. Quantitative estimation of proteins by electrophoresis in antibody-containing agarose gel . Anal Biochem . 1965;10:358.Crossref 24. Rossi E, Mondonico P, Lombari A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometers . Thromb Res . 1988;52:453-468.Crossref 25. Hull R, Carter C, Jay R, et al. The diagnosis of acute recurrent deep vein thrombosis: a diagnostic challenge . Circulation . 1983;67:901-906.Crossref 26. Hull R, Hirsh J, Carter C, et al. Pulmonary angiography, ventilation lung scanning and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan . Ann Intern Med . 1983;98:891-899.Crossref 27. Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer . Am J Clin Pathol . 1988;89:19-23. 28. Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidinerich glycoprotein: mechanism and role in the neutralization of heparin in plasma . J Biol Chem . 1983;258:3803-3808. 29. Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins: an important mechanism for heparin resistance . Thromb Haemost . 1992;67:639-643.

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jan 10, 1994

References